Pulmonary arterial hypertension (PAH) is a multifactorial disease that remains without cure and is characterized by vascular injury, vasoconstriction, and vessel wall remodeling with resultant right ventricular (RV) hypertrophy and eventual failure. A growing body of recent literature has implicated lung inflammation as a critical determinant underlying the development of PAH. Macrophages (M?s), in particular, are prominent components of inflammatory infiltrates observed in the lungs of patients with PAH as well as in animal models of disease. Macrophages respond to environmental signals with remarkable plasticity and undergo different forms of polarized activation that can be broadly categorized as classically-activated (M1) and alternatively- activated (M2). The complexity and diversity of M? activation is rapidly expanding and remains to be fully analyzed. Currently, in addition to M1-M2, there is an anti-inflammatory (regulatory) phenotype that is widely recognized to modulate inflammation and disease. We have demonstrated that alternative activation of M?s is critical for the development of pulmonary hypertension in a hypoxic mouse model (defined as HPH) and that overexpression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), induced a switch in lung M? polarity toward an anti-inflammatory phenotype. Importantly, modulation of early hypoxic inflammation was sufficient to confer protection from HPH under chronic hypoxia. In this proposal, we will test the hypothesis that activated M s promote the vascular injury and vessel wall remodeling underlying the pathogenesis of PAH and will investigate mechanisms of M? activation in HPH, with the goal to identify molecular pathway(s) for therapeutic targeting. We propose the following specific aims: Aim 1: Define the role of M polarization in the pathogenesis of HPH. Aim 2: Define mechanisms by which HO-1 modulates M phenotype and function. Aim 3: Define epigenetic mechanisms that regulate M? phenotype in HPH and identify therapeutic targets.